Over the past 35 years techniques to identify and revascularize ischemic myocardium have been developed to a high level. However, despite such efforts, a mass epidemic of congestive heart failure (CHF) due to coronary disease has developed. Five million Americans suffer from CHF with 550,000 new cases diagnosed each year. Sixty-eight percent of these cases are due to coronary disease. After myocardial infarction (MI) CHF is preceded by infarct expansion, progressive generalized left ventricular (LV) dilatation and contractile dysfunction. This deleteriously progressive phenomenon has been termed post-infarction LV remodeling.
Once the remodeling process is established and symptoms of CHF ensue, five year survival, even with the most aggressive medical and surgical therapy is about 50%. These dismal results have generated a strong interest in developing mechanical strategies for preventing infarct expansion, the resulting LV dilation and failure.
Recent work in chronic large animal heart failure models has demonstrated early restraint to prevent infarct stretching significantly limits ventricular dilation and preserves function. Despite compelling experimental data these techniques currently have limited clinical applicability due to an inability to identify patients early (days after infarction) at risk for remodeling. While infarct size has long been understood to correlate with the ultimate degree of ventricular remodeling, it is a difficult parameter to quantify particularly early after reperfusion therapy.
Apoptosis, or programmed cell death, is known to play a role in the decline of ventricular function in heart failure, for example, in myocardial infarction and heart transplant rejection. In addition, apoptosis is implicated in the disruption of atherosclerotic plaques, which account for more than two-thirds of acute coronary events; plaques that are vulnerable to rupture can demonstrate large necrotic cores and positive remodeling of the sclerotic vessel. Apoptosis comprises a series of genetically programmed events, and is potentially reversible or can otherwise be responsive to intervention, and therefore techniques for detecting apoptotic potential can be used to identify suitable targets for antiapoptotic intervention. Using animal models, antiapoptotic intervention has been shown to delay, prevent the occurrence of, or minimize the severity of heart failure.
Numerous molecular methods for identifying vulnerable atherosclerotic lesions or programmed cell death in myocardial infarction and heart transplant tissue. Wu J C, Narula J, Curr Op in Biotech. 2007, 18:1-3. For example, recent studies have used measurements of matrix metalloproteinase (MMP) expression to identify atherosclerotic plaques that are prone to rupture. See Hartung D, et al., Eur J Nucl Med Mol Imaging. 2007 June; 34 Suppl 1:S1-8. Radiolabeled Annexin A5, a protein that has been proposed to predict the likelihood of acute vascular events, has been used for the noninvasive imaging of atherosclerosis in transgenic mouse models (Isobe S, et al., J Nucl Med. 2006 September; 47(9):1497-505), and for the noninvasive detection of programmed cell death in heart failure patients (Kietselaer B L, J Nucl Med. 2007 April; 48(4): 562-7). However, molecular methods have proven to be of limited efficacy and, importantly, do not enable early-stage detection of coronary events. Early detection of possible plaque rupture and early assessment of myocardial injury would permit timely intervention and preserve a wider range of therapeutic options with respect to a given patient.
Given the extremely widespread prevalence of coronary disease and the uncertainty surrounding both the extent of myocardial injury following an ischemic event and the stability of ostensibly non-threatening vascular occlusions, methods and devices for the accurate in vivo assessment of mitochondrial function would be of considerable clinical value.